Quantifying the activity profile of ASO and siRNA conjugates in glioblastoma xenograft tumors in vivo.

Autor:	Sarli SL; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., Fakih HH; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., Kelly K; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., Devi G; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., Rembetsy-Brown JM; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., McEachern HR; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., Ferguson CM; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., Echeverria D; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., Lee J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., Sousa J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA., Sleiman HF; Department of Chemistry, McGill University, Montréal, Québec, Canada., Khvorova A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Watts JK; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2024 May 22; Vol. 52 (9), pp. 4799-4817.
DOI:	10.1093/nar/gkae260
Abstrakt:	Glioblastoma multiforme is a universally lethal brain tumor that largely resists current surgical and drug interventions. Despite important advancements in understanding GBM biology, the invasiveness and heterogeneity of these tumors has made it challenging to develop effective therapies. Therapeutic oligonucleotides-antisense oligonucleotides and small-interfering RNAs-are chemically modified nucleic acids that can silence gene expression in the brain. However, activity of these oligonucleotides in brain tumors remains inadequately characterized. In this study, we developed a quantitative method to differentiate oligonucleotide-induced gene silencing in orthotopic GBM xenografts from gene silencing in normal brain tissue, and used this method to test the differential silencing activity of a chemically diverse panel of oligonucleotides. We show that oligonucleotides chemically optimized for pharmacological activity in normal brain tissue do not show consistent activity in GBM xenografts. We then survey multiple advanced oligonucleotide chemistries for their activity in GBM xenografts. Attaching lipid conjugates to oligonucleotides improves silencing in GBM cells across several different lipid classes. Highly hydrophobic lipid conjugates cholesterol and docosanoic acid enhance silencing but at the cost of higher neurotoxicity. Moderately hydrophobic, unsaturated fatty acid and amphiphilic lipid conjugates still improve activity without compromising safety. These oligonucleotide conjugates show promise for treating glioblastoma. (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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